title: A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial.
abstract: BACKGROUND
  Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.
  
  
  METHODS
  A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates.
  
  
  CONCLUSIONS
  Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic.
  
  
  BACKGROUND
  ISRCTN45190901.
authors.affiliation: Interdepartmental Division of Critical Care Medicine and Departments of Pharmacy, University of Toronto, Toronto, Ontario, Canada. burnsk@smh.toronto.on.ca
authors.forename: Karen E A
authors.initials: KE
authors.lastname: Burns
authors.forename: Clarence
authors.initials: C
authors.lastname: Chant
authors.forename: Orla
authors.initials: O
authors.lastname: Smith
authors.forename: Brian
authors.initials: B
authors.lastname: Cuthbertson
authors.forename: Robert
authors.initials: R
authors.lastname: Fowler
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Cook
authors.forename: Peter
authors.initials: P
authors.lastname: Kruger
authors.forename: Steve
authors.initials: S
authors.lastname: Webb
authors.forename: Jamal
authors.initials: J
authors.lastname: Alhashemi
authors.forename: Guillermo
authors.initials: G
authors.lastname: Dominguez-Cherit
authors.forename: Carlos
authors.initials: C
authors.lastname: Zala
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Rubenfeld
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
mesh_terms: D000208:Acute Disease; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D001118:Argentina; D001315:Australia; D002170:Canada; D003299:Cooperative Behavior; D003422:Critical Care; D016638:Critical Illness; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005464:Fluorobenzenes / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D007258:Informed Consent; D008800:Mexico; D009520:New Zealand; D018579:Patient Selection; D010865:Pilot Projects; D011743:Pyrimidines / Q000627:therapeutic use*; D012107:Research Design; D012121:Respiration, Artificial; D000068718:Rosuvastatin Calcium; D012529:Saudi Arabia; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium